Skip to main content
Log in

Antithrombotic activities of sulforaphane via inhibiting platelet aggregation and FIIa/FXa

  • Research Article
  • Published:
Archives of Pharmacal Research Aims and scope Submit manuscript

Abstract

Sulforaphane (SFN), a natural isothiocyanate that is present in cruciferous vegetables such as broccoli and cabbage, is effective in preventing carcinogenesis, diabetes and inflammatory responses. Here, the anticoagulant activities of SFN were examined by monitoring activated partial thromboplastin time (aPTT), prothrombin time, and the activities of thrombin (Factor IIa, FIIa) and activated factor X (FXa). And, the effects of SFN on expression of plasminogen activator inhibitor type 1 (PAI-1) and tissue-type plasminogen activator (t-PA) were evaluated in tumor necrosis factor-α activated human umbilical vein endothelial cells (HUVECs). Treatment with SFN resulted in prolonged aPTT and PT and inhibition of the activities of thrombin and FXa, as well as inhibited production of thrombin and FXa in HUVECs. In addition, SFN inhibited thrombin-catalyzed fibrin polymerization and platelet aggregation. SFN also elicited anticoagulant effects in mice. In addition, treatment with SFN resulted in significant reduction of the PAI-1 to t-PA ratio. Collectively, SFN possesses antithrombotic activities and offers a basis for development of a novel anticoagulant.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Fig. 1
Fig. 2
Fig. 3

Similar content being viewed by others

References

  • Bae, J.S. 2011. Antithrombotic and profibrinolytic activities of phloroglucinol. Food and Chemical Toxicology 49: 1572–1577.

    Article  CAS  PubMed  Google Scholar 

  • Bae, J.S., and A.R. Rezaie. 2008. Protease activated receptor 1 (PAR-1) activation by thrombin is protective in human pulmonary artery endothelial cells if endothelial protein C receptor is occupied by its natural ligand. Thrombosis and Haemostasis 100: 101–109.

    CAS  PubMed Central  PubMed  Google Scholar 

  • Berk, B.C., J.I. Abe, W. Min, J. Surapisitchat, and C. Yan. 2001. Endothelial atheroprotective and anti-inflammatory mechanisms. Ann N Y Acad Sci 947: 93–109. discussion 109-11 (2001).

    Article  CAS  PubMed  Google Scholar 

  • Dahlback, B. 2000. Blood coagulation. Lancet 355: 1627–1632.

    Article  CAS  PubMed  Google Scholar 

  • Davie, E.W. 1995. Biochemical and molecular aspects of the coagulation cascade. Thrombosis and Haemostasis 74: 1–6.

    CAS  PubMed  Google Scholar 

  • Davie, E.W., K. Fujikawa, and W. Kisiel. 1991. The coagulation cascade: initiation, maintenance, and regulation. Biochemistry 30: 10363–10370.

    Article  CAS  PubMed  Google Scholar 

  • Dejana, E., A. Callioni, A. Quintana, and G. De Gaetano. 1979. Bleeding time in laboratory animals. II. A comparison of different assay conditions in rats. Thrombosis Research 15: 191–197.

    Article  CAS  PubMed  Google Scholar 

  • Despotis, G.J., G. Gravlee, K. Filos, and J. Levy. 1999. Anticoagulation monitoring during cardiac surgery: a review of current and emerging techniques. Anesthesiology 91: 1122–1151.

    Article  CAS  PubMed  Google Scholar 

  • Esmon, C.T. 2005. The interactions between inflammation and coagulation. British Journal of Haematology 131: 417–430.

    Article  CAS  PubMed  Google Scholar 

  • Esmon, C.T., K. Fukudome, T. Mather, W. Bode, L.M. Regan, D.J. Stearns-Kurosawa, and S. Kurosawa. 1999. Inflammation, sepsis, and coagulation. Haematologica 84: 254–259.

    CAS  PubMed  Google Scholar 

  • Fahey, J.W., and P. Talalay. 1999. Antioxidant functions of sulforaphane: A potent inducer of Phase II detoxication enzymes. Food and Chemical Toxicology 37: 973–979.

    Article  CAS  PubMed  Google Scholar 

  • Fareed, J., I. Thethi, and D. Hoppensteadt. 2012. Old versus new oral anticoagulants: Focus on pharmacology. Annual Review of Pharmacology and Toxicology 52: 79–99.

    Article  CAS  PubMed  Google Scholar 

  • Fares, A. 2013. Winter cardiovascular diseases phenomenon. North American Journal of Medical Sciences 5: 266–279.

    Article  PubMed Central  PubMed  Google Scholar 

  • Fischer, K.G. 2007. Essentials of anticoagulation in hemodialysis. Hemodialysis International 11: 178–189.

    Article  PubMed  Google Scholar 

  • Ghosh, S., M. Ezban, E. Persson, U. Pendurthi, U. Hedner, and L.V. Rao. 2007. Activity and regulation of factor VIIa analogs with increased potency at the endothelial cell surface. Journal of Thrombosis and Haemostasis 5: 336–346.

    Article  CAS  PubMed  Google Scholar 

  • Hamaguchi, E., T. Takamura, A. Shimizu, and Y. Nagai. 2003. Tumor necrosis factor-alpha and troglitazone regulate plasminogen activator inhibitor type 1 production through extracellular signal-regulated kinase- and nuclear factor-kappaB-dependent pathways in cultured human umbilical vein endothelial cells. Journal of Pharmacology and Experimental Therapeutics 307: 987–994.

    Article  CAS  PubMed  Google Scholar 

  • Harbrecht, U. 2011. Old and new anticoagulants. Hamostaseologie 31: 21–27.

    Article  CAS  PubMed  Google Scholar 

  • Heiss, E., C. Herhaus, K. Klimo, H. Bartsch, and C. Gerhauser. 2001. Nuclear factor kappa B is a molecular target for sulforaphane-mediated anti-inflammatory mechanisms. Journal of Biological Chemistry 276: 32008–32015.

    Article  CAS  PubMed  Google Scholar 

  • Jauch, E.C., J.L. Saver, H.P. Adams Jr, A. Bruno, J.J. Connors, B.M. Demaerschalk, P. Khatri, P.W. Mcmullan Jr, A.I. Qureshi, K. Rosenfield, P.A. Scott, D.R. Summers, D.Z. Wang, M. Wintermark, and H. Yonas. 2013. Guidelines for the early management of patients with acute ischemic stroke: a guideline for healthcare professionals from the American Heart Association/American Stroke Association. Stroke 44: 870–947.

    Article  PubMed  Google Scholar 

  • Jayakumar, T., W.F. Chen, W.J. Lu, D.S. Chou, G. Hsiao, C.Y. Hsu, J.R. Sheu, and C.Y. Hsieh. 2013. A novel antithrombotic effect of sulforaphane via activation of platelet adenylate cyclase: ex vivo and in vivo studies. Journal of Nutritional Biochemistry 24: 1086–1095.

    Article  CAS  PubMed  Google Scholar 

  • Kaiser, L., and H.V. Sparks Jr. 1987. Endothelial cells. Not just a cellophane wrapper. Archives of Internal Medicine 147: 569–573.

    Article  CAS  PubMed  Google Scholar 

  • Killeen, M.E., J.A. Englert, D.B. Stolz, M. Song, Y. Han, R.L. Delude, J.A. Kellum, and M.P. Fink. 2006. The phase 2 enzyme inducers ethacrynic acid, DL-sulforaphane, and oltipraz inhibit lipopolysaccharide-induced high-mobility group box 1 secretion by RAW 264.7 cells. Journal of Pharmacology and Experimental Therapeutics 316: 1070–1079.

    Article  CAS  PubMed  Google Scholar 

  • Kim, S.Y., S. Kim, J.M. Kim, E.H. Jho, S. Park, D. Oh, and H.S. Yun-Choi. 2011. PKC inhibitors RO 31-8220 and Go 6983 enhance epinephrine-induced platelet aggregation in catecholamine hypo-responsive platelets by enhancing Akt phosphorylation. BMB Report 44: 140–145.

    Article  CAS  Google Scholar 

  • Kim, T.H., S.K. Ku, and J.S. Bae. 2012. Antithrombotic and profibrinolytic activities of eckol and dieckol. Journal of Cellular Biochemistry 113: 2877–2883.

    Article  CAS  PubMed  Google Scholar 

  • Lee, K.H. 2000. Research and future trends in the pharmaceutical development of medicinal herbs from Chinese medicine. Public Health Nutrition 3: 515–522.

    Article  CAS  PubMed  Google Scholar 

  • Lin, W., R.T. Wu, T. Wu, T.O. Khor, H. Wang, and A.N. Kong. 2008. Sulforaphane suppressed LPS-induced inflammation in mouse peritoneal macrophages through Nrf2 dependent pathway. Biochemical Pharmacology 76: 967–973.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Lopez, S., F. Peiretti, B. Bonardo, I. Juhan-Vague, and G. Nalbone. 2000. Effect of atorvastatin and fluvastatin on the expression of plasminogen activator inhibitor type-1 in cultured human endothelial cells. Atherosclerosis 152: 359–366.

    Article  CAS  PubMed  Google Scholar 

  • Mann, K.G., K. Brummel, and S. Butenas. 2003. What is all that thrombin for? Journal of Thrombosis and Haemostasis 1: 1504–1514.

    Article  CAS  PubMed  Google Scholar 

  • Monroe, D.M., M. Hoffman, and H.R. Roberts. 2002. Platelets and thrombin generation. Arteriosclerosis, Thrombosis, and Vascular Biology 22: 1381–1389.

    Article  CAS  PubMed  Google Scholar 

  • Nowak, P., H.M. Zbikowska, M. Ponczek, J. Kolodziejczyk, and B. Wachowicz. 2007. Different vulnerability of fibrinogen subunits to oxidative/nitrative modifications induced by peroxynitrite: functional consequences. Thrombosis Research 121: 163–174.

    Article  CAS  PubMed  Google Scholar 

  • Oh, C.H., J.I. Shin, S.J. Mo, S.J. Yun, S.H. Kim, and Y.H. Rhee. 2013. Antiplatelet activity of l-sulforaphane by regulation of platelet activation factors, glycoprotein IIb/IIIa and thromboxane A2. Blood Coagulation & Fibrinolysis 24: 498–504.

    Article  CAS  Google Scholar 

  • Philip-Joet, F., M.C. Alessi, C. Philip-Joet, M. Aillaud, J.R. Barriere, A. Arnaud, and I. Juhan-Vague. 1995. Fibrinolytic and inflammatory processes in pleural effusions. European Respiratory Journal 8: 1352–1356.

    Article  CAS  PubMed  Google Scholar 

  • Popa, C., M.G. Netea, P.L. Van Riel, J.W. Van Der Meer, and A.F. Stalenhoef. 2007. The role of TNF-alpha in chronic inflammatory conditions, intermediary metabolism, and cardiovascular risk. Journal of Lipid Research 48: 751–762.

    Article  CAS  PubMed  Google Scholar 

  • Quinn, C., J. Hill, and H. Hassouna. 2000. A guide for diagnosis of patients with arterial and venous thrombosis. Clinical Laboratory Science 13: 229–238.

    CAS  PubMed  Google Scholar 

  • Rao, L.V., S.I. Rapaport, and M. Lorenzi. 1988. Enhancement by human umbilical vein endothelial cells of factor Xa-catalyzed activation of factor VII. Blood 71: 791–796.

    CAS  PubMed  Google Scholar 

  • Ross, R. 1999. Atherosclerosis—an inflammatory disease. New England Journal of Medicine 340: 115–126.

    Article  CAS  PubMed  Google Scholar 

  • Schleef, R.R., M.P. Bevilacqua, M. Sawdey, M.A. Gimbrone Jr, and D.J. Loskutoff. 1988. Cytokine activation of vascular endothelium. Effects on tissue-type plasminogen activator and type 1 plasminogen activator inhibitor. Journal of Biological Chemistry 263: 5797–5803.

    CAS  PubMed  Google Scholar 

  • Schouten, M., W.J. Wiersinga, M. Levi, and T. Van Der Poll. 2008. Inflammation, endothelium, and coagulation in sepsis. Journal of Leukocyte Biology 83: 536–545.

    Article  CAS  PubMed  Google Scholar 

  • Sugo, T., C. Nakamikawa, S. Tanabe, and M. Matsuda. 1995. Activation of prothrombin by factor Xa bound to the membrane surface of human umbilical vein endothelial cells: its catalytic efficiency is similar to that of prothrombinase complex on platelets. Journal of Biochemistry 117: 244–250.

    Article  CAS  PubMed  Google Scholar 

  • Van Den Berg, E.A., E.D. Sprengers, M. Jaye, W. Burgess, T. Maciag, and V.W. Van Hinsbergh. 1988. Regulation of plasminogen activator inhibitor-1 mRNA in human endothelial cells. Thrombosis and Haemostasis 60: 63–67.

    PubMed  Google Scholar 

  • Van Hinsbergh, V.W., T. Kooistra, E.A. Van Den Berg, H.M. Princen, W. Fiers, and J.J. Emeis. 1988. Tumor necrosis factor increases the production of plasminogen activator inhibitor in human endothelial cells in vitro and in rats in vivo. Blood 72: 1467–1473.

    PubMed  Google Scholar 

Download references

Acknowledgments

This study was supported by the National Research Foundation of Korea (NRF) funded by the Korean government [MSIP] (Grant Nos. 2013-067053).

Conflict of interest

The authors have no conflict of interest to declare.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Jong-Sup Bae.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Ku, SK., Bae, JS. Antithrombotic activities of sulforaphane via inhibiting platelet aggregation and FIIa/FXa. Arch. Pharm. Res. 37, 1454–1463 (2014). https://doi.org/10.1007/s12272-014-0403-8

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12272-014-0403-8

Keywords

Navigation